Key result
Crenigacestat completely inhibited osteogenic differentiation and matrix mineralization of human valve interstitial cells from patients with calcific aortic valve disease in vitro.
Why the study?
Calcific aortic valve disease lacks targeted therapy, and inhibiting osteogenic differentiation of valve interstitial cells via Notch pathway inhibitors may suppress calcification.
Does crenigacestat or CB-103 inhibit osteogenic differentiation in human valve interstitial cells from patients with calcific aortic valve disease in vitro?
Does crenigacestat or CB-103 inhibit osteogenic differentiation in human valve interstitial cells from patients with calcific aortic valve disease in vitro?
p-value: p=<0.001
Crenigacestat, a Notch signaling inhibitor, effectively suppresses osteogenic differentiation of human valve interstitial cells in vitro, suggesting potential as a targeted therapy for calcific aortic valve disease.
Calcific aortic valve disease (CAVD) is one of the dangerous forms of vascular calcification. CAVD leads to calcification of the aortic valve and disturbance of blood flow. Despite high mortality, there is no targeted therapy against CAVD or vascular calcification. Osteogenic differentiation of valve interstitial cells (VICs) is one of the key factors of CAVD progression and inhibition of this process seems a fruitful target for potential therapy. By our previous study we assumed that inhibitors of Notch pathway might be effective to suppress aortic valve leaflet calcification. We tested CB-103 and crenigacestat (LY3039478), two selective inhibitors of Notch-signaling, for suppression of osteogenic differentiation of VICs isolated from patients with CAVD in vitro . Effect of inhibitors were assessed by the measurement of extracellular matrix calcification and osteogenic gene expression. For effective inhibitor (crenigacestat) we also performed MTT and proteomics study for better understanding of its effect on VICs in vitro . CB-103 did not affect osteogenic differentiation. Crenigacestat completely inhibited osteogenic differentiation (both matrix mineralization and Runx2 expression) in the dosages that had no obvious cytotoxicity. Using proteomics analysis, we found several osteogenic differentiation-related proteins associated with the effect of crenigacestat on VICs differentiation. Taking into account that crenigacestat is FDA approved for clinical trials for anti-tumor therapy, we argue that this drug could be considered as a potential inhibitor of cardiovascular calcification.
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Lobov et al. (2022) studied Calcific aortic valve disease (n=3). Crenigacestat (LY3039478) vs. Osteogenic medium (control) was evaluated on Extracellular matrix calcification (Alizarin Red stain) (p=<0.001). Crenigacestat completely inhibited osteogenic differentiation and matrix mineralization of human valve interstitial cells from patients with calcific aortic valve disease in vitro.
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